Background

Afebrile pneumonia syndrome (APS) is a relatively uncommon disease of neonates and infants younger than 6 months. A correlation has been noted between low birthweight, prematurity, and low socioeconomic status and the incidence of APS.

APS was first described as a vertically transmitted infection of newborns and young infants by the female genital tract pathogens Chlamydia trachomatis, cytomegalovirus (CMV), and Ureaplasma urealyticum. Other potential causes of the syndrome have since been recognized, including respiratory syncytial virus (RSV), parainfluenza virus, adenovirus, human metapneumovirus,
[1, 2] human bocavirus,
[1] Pneumocystis jiroveci,
[3] and, perhaps, Simkania negevensis.
[4]

APS is typified by chlamydial pneumonitis,
[5] with acute or subacute onset of a chronic, afebrile or minimally febrile, diffuse pulmonary process associated with mild peripheral eosinophilia and elevated serum immunoglobulin levels. Symptoms are usually nonspecific and include cough, tachypnea, irritability, poor feeding, and low-grade fever or lack of fever, making differentiating among the above etiologies of APS and among APS and other pulmonary processes difficult. (See Clinical Presentation.)

Acutely, APS is generally a benign and self-limiting disease. In such cases, infants often have viral illness, which does not respond to antibiotic therapy, but differentiating bacterial from viral illness is often difficult. Consider empiric antibiotic therapy if the potential benefits of early intervention outweigh the risks of unnecessary treatment. (See Medication, as well as Treatment and Management.)

Knowledge of the likely pathogens can help determine the tests needed to confirm diagnosis. (See Workup.)

Long-term prognosis for significant morbidity is high. Affected individuals have a high rate of obstructive airway disease later in life. (See Prognosis.)

Etiology

Although many organisms can cause afebrile pneumonia syndrome (APS), this article focuses on Chlamydia trachomatis, cytomegalovirus (CMV), and Ureaplasma urealyticum, which are vertically transmitted to newborns during passage through the birth canal or, in the case of CMV, also during breastfeeding. In recent series, C trachomatis was identified as the causative agent in 5-90% of patients, CMV was identified in 0-23%, and U urealyticum was identified in 0-21%.

Chlamydia trachomatis

C trachomatis colonizes the genital tracts of 2-13% of pregnant women (with higher rates among unmarried women with lower socioeconomic status, a greater number of sexual partners, and younger age) and is transmitted to more than 50% of their infants. Portals of entry include the eyes, nasopharynx, respiratory tract, and vagina. If left untreated, 5-13% of infants colonized by C trachomatis develop pneumonia.

Cytomegalovirus infection

CMV has been identified in the genital tracts of 11-28% of women close to term and in breast milk of 10-20% of mothers who are breastfeeding. More than 50% of exposed infants become infected, but development of pneumonia is uncommon.

Ureaplasma urealyticum

U urealyticum colonizes the genital tract of 40-80% of pregnant women (with risk factors similar to those for C trachomatis) and the mucous membranes of 16% of newborns with low birthweight and 8-11% of infants who weigh more than 2500 g at birth. How frequently U urealyticum causes pneumonia remains unclear.

Other pathogens

Other common causative agents associated with seasonal or epidemic occurrences include respiratory syncytial virus (RSV), parainfluenza, human bocavirus, human metapneumovirus, and adenovirus. These organisms cause APS, as well as more typical bronchiolitis, pneumonia, pneumonitis, laryngotracheobronchitis, and conjunctivitis/pharyngitis. In contrast to the vertically transmitted etiologies, these viruses cause highly contagious infections that are horizontally transmitted. RSV infection is the most commonly identified cause of pneumonia (typically febrile) in neonates and infants younger than 6 months (79% of cases) in the United States. This frequency may be artificially elevated because of the ease with which this diagnosis can be made.

P jiroveci is increasingly being recognized as a cause of APS. Among newborns and infants, P jiroveci appears to cause asymptomatic infection more commonly than it causes any recognizable disease. The extent to which human bocavirus, human metapneumovirus, and S negevensis (a Chlamydia -like organism) cause APS will be determined as they become more easily identified in the clinical setting.

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Epidemiology

The frequency of APS is unknown. Vertically transmitted APS is more common among children of lower socioeconomic status and those who have the risk factors listed above. All APS infections tend to be more common in regions where crowding and poor hygiene predominate.

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Prognosis

APS is generally a benign and self-limiting disease. However, one long-term follow-up study showed a 3.4% mortality rate among 205 infants younger than 3 months who had APS.
[6] In the study, 46% of infants who survived experienced one or more episodes of wheezing by age 4 years, and 15% of infants had persistently abnormal chest radiographic findings for at least 12 months.

Of children with APS who were monitored for 5 years, 60% had abnormal pulmonary function test results. Abnormal results occurred irrespective of prematurity, atopy, or the etiologic agent associated with the APS. Evidence indicates that respiratory infections in infancy predispose patients to obstructive airway disease later in life.

Immediate prognosis is good for more than 95% of affected infants, although long-term prognosis for significant morbidity is high. Following a 5-year follow-up period, 60% of infants have abnormal pulmonary function test findings. More than one half of infants with chlamydial pneumonitis have obstructive airway disease and physician-diagnosed asthma by age 7 years.

Michael R Bye, MD Professor of Clinical Pediatrics, State University of New York at Buffalo School of Medicine; Attending Physician, Pediatric Pulmonary Division, Women's and Children's Hospital of Buffalo

Disclosure: Received honoraria from Genentech for speaking and teaching; Received honoraria from Genentech for consulting; Partner received consulting fee from Boston Scientific for consulting; Received honoraria from Gilead for speaking and teaching; Received consulting fee from Caremark for consulting; Received honoraria from Vertex Pharmaceuticals for speaking and teaching.